Malformations of the heart are the most common, serious birth defects, and an important cause of morbidity and mortality throughout the lifespan of affected individuals. Despite the public health significance of these conditions, the causes of congenital heart defects are poorly understood and primary prevention methods are lacking. Like other structural malformations, such as neural tube defects and facial clefts, most non-syndromic cases of CHDs are thought to be genetically complex conditions determined by the effects of multiple environmental and genetic factors. However, there are few established risk factors for non-syndromic CHDs in general, or for subgroups such as the CTDs. This situation is not unlike that for several other common, complex diseases, for which recent genome-wide association studies (GWAS) have provided strong evidence for the existence of common, disease-related, gene variants. Hence, application of genome-wide approaches to the study of CHDs is of extreme interest and has the potential to significantly advance our understanding of the pathways that are involved in the development of these conditions. We propose to perform the statistical analyses required to complete a GWAS of a subgroup of CHDs referred to as conotruncal heart defects (CTDs). This subgroup accounts for approximately 1/3rd of all CHDs, and there is a substantial body of data, derived from both animal and human studies, indicating that the cardiac phenotypes that fall within it are more closely related to each other than to other forms of CHDs. Through the ongoing efforts of this research team, SNP genotyping data from the Illumina 550K chip for 800 CTD case-parent triads are in hand and awaiting analyses to: (1) Identify maternal and inherited (i.e. case) genotypes that are associated with CTDs, and (2) Identify pathways and gene sets that are associated with CTDs. PUBLIC HEALTH RELEVANCE: Conotruncal heart defects are common, serious malformations of the heart that have a significant impact on affected individuals, their families and society. Despite the health significance of these conditions, the causes of conotruncal heart defects are poorly understood and primary prevention methods are lacking. The work proposed in this application will help to indentify genes that are associated with the risk that a child will be born with one of these conditions.